Within target tissues 17 beta-estradiol (E2) is destined to be metabolized by specific enzymes as well as being bound by its receptor and translocated into the nucleus. Once within the nucleus E2 may share a metabolic fate in addition to being associated with salt extractable and salt resistant components. At the present time this laboratory and a few others have documented two E2 metabolic conversions which occur in target tissues. These consist of estrogen-3-sulfurylation and oxido-reduction at C-17. Since the products of these enzymic reactions bind less tightly to the receptor, the activities of both estrogen sulfotransferase and E2 dehydrogenase may be related to the tissues response to E2. Estrogen sulfotransferase has been postulated as a cytosolic enzyme having the function of preventing the adsorption of estrogen to receptor in the uterus and in breast tumors. It is proposed to purify this enzyme from these tissues and establish its kinetic and specificity properites, and to investigate the role of progesterone (Pg) in the induction of this enzyme in cell cultures from breast tumors and endometrial adenocarcinoma. Utilizing these cultures it will be determined whether the "down-regulation" of E2 receptor (E2R) by Pg is a property of both endometrial and breast tumor cells and whether this function is carried out through the induction of the above cytosolic enzymes or by alteration in the nuclear fate of E2R. To this end, detailed studies will be initiated concerning the characteristics of, and cellular function related to, the various classes of nuclear E2 binding (i.e., salt extractable E2 and dextran-coated charcoal revealed E2 and E1 binding, and salt resistant E2 or E1 binding).